Substituted 4-oxo-napthyridine-3-carboxamides: GABA brain receptor ligands

ABSTRACT

The present invention encompasses structures of the Formula                    
     or the pharmaceutically acceptable non-toxic salts thereof wherein: 
     X is hydrogen, halogen, (un)substituted alkyl, (un)substituted alkoxy or amino; and 
     Y is (un)substituted alkyl, aryl, or heteroaryl, 
     which compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, and overdose with benzodiazepine drugs and for enhancement of alertness.

This application is a continuation of U.S. patent application Ser. No.09/634,093, filed Aug. 8, 2000, now U.S. Pat. No. 6,399,604, which is acontinuation of U.S. patent application Ser. No. 09/139,456, filed Aug.25, 1998, now U.S. Pat. No. 6,143,760, which claims priority from U.S.Provisional Appl. No. 60/056,799, filed Aug. 25, 1997.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to substituted 4-oxo-napthyridine-3-carboxamidesand, in particular, such compounds which selectively bind to GABAareceptors. This invention also relates to pharmaceutical compositionscomprising such compounds and to the use of such compounds in enhancingalertness and treating anxiety, overdoses of benzodiazepine-type drugs,Down Syndrome, and sleep, seizure and cognitive disorders.

2. Description of the Related Art

γ-Aminobutyric acid (GABA) is regarded as one of the major inhibitoryamino acid transmitters in the mammalian brain. Over 40 years haveelapsed since its presence in the brain was demonstrated (Roberts &Frankel, J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187:65-69, 1950). Since that time, an enormous amount of effort has beendevoted to implicating GABA in the etiology of seizure disorders, sleep,anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8:21-44, 1985). Widely, although unequally, distributed through themammalian brain, GABA is said to be a transmitter at approximately 30%of the synapses in the brain. GABA mediates many of its actions througha complex of proteins localized both on cell bodies and nerve endings;these are called GABAa receptors. Postsynaptic responses to GABA aremediated through alterations in chloride conductance that generally,although not invariably, lead to hyperpolarization of the cell. Drugsthat interact at the GABAa receptor can possess a spectrum ofpharmacological activities depending on their abilities to modify theactions of GABA.

The 1,4-Benzodiazepines, such as diazepam, continue to be among the mostwidely used drugs in the world as anxiolytics, sedative-hypnotics,muscle relaxants, and anticonvulsants. A number of these compounds areextremely potent drugs; such potency indicates a site of action with ahigh affinity and specificity for individual receptors. Earlyelectro-physiological studies indicated that a major action ofbenzodiazepines was enhancement of GABAergic inhibition. Presently,those compounds possessing activity similar to the benzodiazepines arecalled agonists. Compounds possessing activity opposite tobenzodiazepines are called inverse agonists, and the compounds blockingboth types of activity have been termed antagonists.

The GABAa receptor subunits have been cloned from bovine and human cDNAlibraries (Schoenfield et al., 1988; Duman et al., 1989). A number ofdistinct cDNAs were identified as subunits of the GABAa receptor complexby cloning and expression. These are categorized into α, β, γ, δ, ε, andprovide a molecular basis for the GABAa receptor heterogeneity anddistinctive regional pharmacology (Shivvers et al., 1980; Levitan etal., 1989). The γ subunit appears to enable drugs like benzodiazepinesto modify the GABA responses (Pritchet et al., 1989). The presence oflow Hill coefficients in the binding of ligands to the GABAa receptorindicates unique profiles of subtype specific pharmacological action.

With the discovery of the “receptor” for the benzodiazepines and thesubsequent definition of the nature of the interaction between GABA andthe benzodiazepines, it appears that the behaviorally importantinteractions of the benzodiazepines with different neurotransmittersystems are due in a large part to the enhanced ability of GABA itselfto modify these systems. Each modified system, in turn, may beassociated with the expression of a behavior. Depending on the mode ofinteraction, these compounds are capable of producing a spectrum ofactivities (either sedative, anxiolytic, and anticonvulsant, orwakefulness, seizures, and anxiety).

Various 1,4-dihydro-4-oxo-1,5-naphthyridine-3-carboxylic acids andesters have been disclosed. See, for example, Eur. J. Med. Chem.-Chim.Ther. (1977), 12 (6), 549-55.

Polish Patent No. 125299 discloses compounds of the formula:

wherein N denotes a ring nitrogen in the 5- or 6-position, and R is CO₂Hor CO₂Et.

Several 1,4-dihydro-4-oxo-1,5-napthyridine-3-carboxamide derivatives ofpenicillin said to possess antibacterial activity have been disclosed.For example, German Patent No. DD 279887 discloses a compound of theformula

Japanese Patent No. 72-45118 discloses ampicillin derivatives of1,4-dihydro-4-oxo-3-naphthyridines.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact witha GABAa binding site, the benzodiazepine receptor.

The invention provides pharmaceutical Compositions comprising compoundsof Formula I. The invention also provides compounds useful in thediagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive andseizure disorders, and overdose with benzodiazepine drugs and forenhancement of alertness. Accordingly, a broad embodiment of theinvention is directed to compounds of Formula I:

wherein:

X is hydrogen, halogen, —OR₁, C₁-C₆ alkyl optionally substituted with upto three groups selected independently from halogen and hydroxy, or—NR₂R₃;

X is phenyl, naphthyl, 1-(5,6,7,8-tetrahydro)naphthyl or4-(1,2-dihydro)indenyl, pyridinyl, pyrimidyl, isoquinolinyl1,2,3,4-tetrahydroisoquinolinyl, benzofuranyl, benzothienyl, each ofwhich is optionally substituted with up to three groups selected fromhalogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, hydroxy, amino,mono or di(C₁-C₆)alkylamino, cyano, nitro, trifluoromethyl ortrifluoromethoxy; or

X represents a carbocyclic group (“the X carbocyclic group”) containingfrom 3-7 members, up to two of which members are optionally hetero atomsselected from oxygen and nitrogen, where the X carbocyclic group isoptionally substituted with one or more groups selected from halogen,alkoxy, mono- or dialkylamino, sulfonamide, azacycloalkyl,cycloalkylthio, alkylthio, phenylthio, or a heterocyclic group;

Y is lower alkyl having 1-8 carbon atoms optionally substituted with upto two groups selected from halogen, alkoxy, mono- or dialkylamino,sulfonamide, azacycloalkyl, cycloalkylthio, alkylthio, phenylthio, aheterocyclic group, —OR₄, —NR₅R₆, SR₇, or aryl; or

Y is a carbocyclic group (“the Y carbocyclic group”) having from 3-7members atoms, where up to three of which members are optionally heteroatoms selected from oxygen and nitrogen and where any member of the Ycarbocyclic group is optionally substituted with halogen, —OR₄, —NR₅R₆,SR₇, aryl or a heterocyclic group;

R₁ is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkylhaving 3-7 carbon atoms, where each alkyl may be optionally substitutedwith —OR₄, or —NR₅R₆;

R₂ and R₃ are the same or different and represent

hydrogen, lower alkyl optionally mono- or disubstituted with alkoxy,aryl, halogen, or mono- or di-lower alkyl;

aryl or aryl(C₁-C₆)alkyl where each aryl is optionally substituted withup to three groups selected from halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆alkoxy, or mono- or di(C₁-C₆)alkylamino;

cycloalkyl having 3-7 carbon atoms optionally mono or disubstituted withhalogen, alkoxy, or mono- or di-lower alkyl; or

—SO₂R₈;

R₄ is as defined for R₁;

R₅ and R₆ carry the same definitions as R₂ and R₃, respectively;

R₇ is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkylhaving 3-7 carbon atoms; and

R₈ is lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbonatoms, or optionally substituted phenyl.

These compounds are highly selective agonists, antagonists or inverseagonists for GABAa brain receptors or prodrugs of agonists, antagonistsor inverse agonists for GABAa brain receptors. These compounds areuseful in the diagnosis and treatment of anxiety, Down Syndrome, sleep,cognitive and seizure disorders, and overdose with benzodiazepine drugsand for enhancement of alertness.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed big the invention can be described bythe general Formula I set forth above.

In Formula I above, —NR₂R₃ can also represent a heterocyclic group suchas, for example, piperidine in the case where R₂ and R₃ together form aC₅-alkylene group. Further, R₂ and R₃ together may represent an alkyleneor alkenylene group optionally containing up to two heteroatoms selectedfrom nitrogen and oxygen. The resulting groups include imidazolyl,pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl.

Similarly, the —NR₅R₆ group in Formula I above can also represent aheterocyclic group such as, for example, piperidine in the case where R₅and R₆ together form a C₅-alkylene group. Further, R₅ and R₆ togethermay represent an alkylene or alkenylene group optionally containing upto two heteroatoms selected from nitrogen and oxygen. The resultinggroups include imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, andpiperidinyl.

Preferred compounds of Formula I are those where X represents(C₁-C₆)alkoxy, more preferably (C₁-C₃)alkoxy. Particularly preferredcompounds of Formula I include methoxy or ethoxy as the X group.

Still other preferred compounds of Formula I include those where the Yis lower alkyl, e.g., methyl or ethyl, substituted with phenyl, pyridyl,or pyrimidinyl. A more preferred Y group is benzyl optionallysubstituted with halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino, or mono-or di(C₁-C₆)alkyl.

Where R₂ and R₃ in Formula I represent optionally substituted aryl oraryl(C₁-C₆)alkyl, the aryl group is preferably phenyl, pyridyl, orpyrimidinyl and the alkyl groups are preferably methyl and ethyl. Morepreferred are benzyl and phenyl. Particularly preferred is benzyl.

Where X is optionally substituted C₁-C₆ alkyl, the alkyl group ispreferably optionally substituted methyl, ethyl, or propyl. Morepreferred are perhalomethyl and trihaloethyl. Preferred halogens arefluorine. Particularly preferred is 2,2,2-trifluoroethyl.

X in Formula I may be an optionally substituted phenyl, naphthyl,1-(5,6,7,8-tetrahydro)naphthyl, 4-(1,2-dihydro)indenyl, pyridinyl,pyrimidyl, isoquinolinyl, benzofuranyl, or benzothienyl group, orpreferably a 1,2,3,4-tetrahydroisoquinolinyl group.

In addition to the compounds of Formula I, the invention encompassescompounds of Formula IA

wherein:

X is

(i) hydrogen, halogen, mono- or dialkylamino, alkoxy,

(ii) a group of the formula:

where G is lower alkylene having 1-6 carbon atoms, or a cyclic group ofthe formula

where n is 0, 1, or 2, and m is an integer of from 1 to 5, with theproviso that the sum of n+m is not less than 1 or greater than 5; and

R₁ is hydrogen, lower alkyl, or (C₃-C₇)cycloalkyl, where the alkyl orcycloalkyl is optionally substituted with halogen, lower alkoxy, ormono- or di(C₁-C₆)alkylamino;

(iii) a group of the formula:

 where

G is as defined above for ii; and

R₂ and R₃ independently represent hydrogen, lower alkyl having 1-6carbon atoms, cycloalkyl having 3-7 carbon atoms, —SO₂R₈ where R₈ is(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, or optionally substituted phenyl, or

R₂ and R₃ together with the nitrogen atom to which they are attachedform a heterocyclic moiety such as imidazolyl, pyrrolidinyl,morpholinyl, piperazinyl, or piperidinyl;

(iv) a group of the formula:

 where

R₂ is as defined above for iii;

R₄ is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkylhaving 3-7 carbon atoms, and may be optionally substituted with one ormore (C₁-C₆)alkoxy or mono- or di(C₁-C₆)alkylamino groups; and

G is as defined above for ii;

(v) a group of the formula:

 where

R₂ and G are as defined above for iv and ii, respectively, and

R₅ and R₆ independently represent hydrogen, lower alkyl having 1-6carbon atoms, cycloalkyl having 3-7 carbon atoms, —SO₂R₈ where R₈ is(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, or optionally substituted phenyl, or

R₅ and R₆ together with the nitrogen atom to which they are attachedform a heterocyclic moiety such as imidazolyl, pyrrolidinyl,morpholinyl, piperazinyl, or piperidinyl;

(vi) a group of the formula:

where G is as defined above for ii; or

(vii) a group of the formula:

where each G is as defined above for ii; and

Y is

(viii) lower alkyl having 1-8 carbon atoms or cycloalkyl having 3-7carbon atoms, any of which may be optionally substituted with one ormore hydroxy, halogen, (C₁-C₆)alkoxy, alkoxyalkoxy where each alkoxy is(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₃-C₇)cycloalkylthio, aryl,heteroaryl, or mono- or di(C₁-C₆)alkylamino groups;

(ix) a group of the formula:

where K is lower alkylene having 1-6 carbon atoms optionally substitutedwith (C₁-C₆)alkyl or alkylene, or a cyclic group of the formula

where K′ independently represents hydrogen or (C₁-C₆)alkyl or alkylene,n is 0, 1, or 2, and m is an integer of from 1 to 5, with the provisothat the sum of n+m is not less than 1 or greater than 5; and

R₉ is hydrogen, lower alkyl, or (C₃-C₇) cycloalkyl, where the alkyl orcycloalkyl is optionally substituted with halogen, lower alkoxy, ormono- or dialkylamino;

(x) a group of the formula:

where K is defined as above in ix;

(xi) a group of the formula:

 where

K is as defined above for ix, and

R₁₃ is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkylhaving 3-7 carbon atoms, where the alkyl and cycloalkyl groups areoptionally substituted with one or more (C₁-C₆)alkoxy or mono- ordi(C₁-C₆)alkylamino groups; and

(xii) a group of the formula:

 where

K is as defined above for ix, and

R₇ is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkylhaving 3-7 carbon atoms; and

(xiii) a group of the formula:

 where

K is as defined above for ix; and

R₁₄ and R₁₅ independently represent hydrogen, lower alkyl having 1-6carbon atoms, cycloalkyl having 3-7 carbon atoms, —SO₂R₈ where R₈ is asdefined above, or

R₁₄ and R₁₅ together with the nitrogen atom to which they are attachedform a heterocyclic moiety such as imidazolyl, pyrrolidinyl,morpholinyl, piperazinyl, or piperidinyl;

(xiv) a group of the formula:

where K and R₁₅ are as defined above in ix and xii, respectively;

(xv) a group of the formula:

 where

K is as defined above for ix;

R₁₀ and R₁₀′ are the same or different and are selected from hydrogen,(C₁-C₆), halogen, hydroxy, lower alkoxy having 1-6 carbon atoms, orcycloalkoxy having 3-7 carbon atoms;

R₁₁, R₁₁′, and R₁₂ are the same or different and are selected fromhydrogen, C₁-C₆ alkyl, halogen, hydroxy, —OR₄, —CR₇(R₉)NR₅R₅,—CR₉(R₁₆)OR₄,

or R₁₁ and R₁₂ taken together with the atoms to which they are attachedform a (hetero)cyclic ring; and

R₁₆ is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkylhaving 3-7 carbon atoms;

(xvi) a group of the formula:

where K is as defined above for ix; and W is heteroaryl;

(xvii) a group of the formula:

 where

K is as defined above for ix; R₁₀ and R₁₁ are as defined above for xv,and

R₁₇ is hydrogen, lower alkyl, or (C₃-C₇)cycloalkyl, where the alkyl orcycloalkyl is optionally substituted with halogen, lower alkoxy, ormono- or di(C₁-C₆)alkylamino;

(xviii) a group of the formula:

where K, R₁₀, R₁₂, and R₁₇ are as defined above;

(xix) a group of the formula:

where each K is independently as defined above for ix and R₁₀ is definedabove;

(xx) a group of the formula:

where K, R₁₀, R₁₁, R₁₄, and R₁₅ are as defined above;

(xxi) a group of the formula:

where K, R₁₀, R₁₂, R₁₄, and R₁₅ are as defined above;

(xxii) pyrimidinyl(C₁-C₆)alkyl or pyridyl(C₁-C₆)alkyl; or

(xxiii) a group of the formula:

where R₁₈ represents hydrogen, amino, mono-, or di(C₁-C₆)alkylamino, orC₁-C₆ alkyl optionally substituted with a R₁₉ where R₁₈ represents:

where V and V′ are independently CH or nitrogen;

A″ is C₁-C₆ alkylene; and R₂₀ is phenyl, pyridyl, or pyrimidinyl, eachof which is optionally mono-, di-, or trisubstituted independently withhalogen, hydroxy, C₁-C₆ alkoxy, amino, or mono- or di(C₁-C₆)alkylamino.

Preferred pyrimidinyl(C₁-C₆)alkyl Y groups are 2- and4-pyrimidinylmethyl. Preferred pyridyl(C₁-C₆)alkyl Y groups are 2- and4-pyridylmethyl.

Preferred benzyl Y groups are those where R₁₈ is amino or a substitutedmethyl or ethyl group. More preferred R₁₈ substituents arepiperazin-1-yl or piperidin-1-yl substituted at the 4-position with ahalogenated benzyl group. Particularly preferred benzyl Y groups are4-[1-[4-(4-Fluorobenzyl)piperazinyl]methyl]benzyl and4-[1-[4-(4-Fluorobenzyl)piperidinyl]methyl]benzyl.

Preferred “X” groups in Formula IA are various quinolinyl,isoquinolinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl groups,e.g., groups of the formulas:

The following formulae are preferred embodiments of the invention:

wherein Y is defined above.

wherein Z represents halogen and Y is as defined above.

wherein R₁ and Y are defined above.

wherein R₂, R₃, and Y are defined above.

wherein R₂, R₈, and Y are defined above.

wherein R₁, G and Y are defined above

wherein R₂, R₃, G, and Y are defined above.

wherein R₂, R₄, G, and Y are defined above.

wherein R₂, R₅, R₆, G, and Y are defined above.

wherein G and Y are defined above.

wherein R₂, G, and Y are defined above.

wherein X is defined above and U is (C₁-C₆)lower alkyl or(C₁-C₆)cycloalkyl.

wherein X, K, and R₁ are defined above.

wherein X and K are defined above.

wherein X, K, and R₄ are defined above.

wherein X, K, and R₇ are defined above.

wherein X, K, R₁₄, and R₁₅ are defined above.

wherein X, K, and R₁₅ are defined above.

wherein:

R₁₀, R₁₀′ are the same or different and may be selected from hydrogen,(C₁-C₆)alkyl, halogen, hydroxy, lower alkoxy having 1-6 carbon atoms, orcycloalkoxy having 3-7 carbon atoms;

R₁₁, R₁₁′, and R₁₂ are the same or different and may be selected fromhydrogen, (C₁-C₆)alkyl, halogen, hydroxy, —OR₄, —CR₇(R₉)N_(R)5R₆,—CR₇(R₉)OR₄; or

R₁₁ and R₁₂ taken together with the atoms to which they are attachedform a (hetero)cyclic ring; and

R₉ is as defined above.

wherein

X and K are defined above; and

W is heteroaryl.

wherein X, K, R₁, R₁₀, and R₁₁ are defined above.

wherein X, K, R₁, R₁₀, and R₁₂ are defined above.

wherein X, K, and R₁₀ are defined above.

wherein X, K, R₁₄, R₁₅, R₁₀ and R₁₁ are defined above.

Preferred compounds of the invention are encompassed by the followingformulae:

where

A is C₁-C₆ alkylene;

R_(a) is phenyl optionally mono-, di-, or trisubstituted with halogen,lower alkyl, lower alkoxy, or mono- or di-C₁-C₆ alkylamino, or mono- ordi-C₁-C₆ alkylamino lower alkyl; and

R_(b) is lower alkyl or lower cycloalkyl.

More preferred compounds of Formula XXVII are those where A ismethylene, R_(a) is phenyl optionally substituted with methyl or ethyl,and R_(b) is lower alkyl. Particularly, preferred compounds of FormulaXXVII are those where A is methylene, R_(a) is phenyl and R_(b) is C₁-C₃alkyl.

wherein

A is C₁-C₆ alkylene;

R_(a) and R_(a)′ are independently phenyl groups optionally mono-, di-,or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- ordi-C₁-C₆ alkylamino, or mono- or di-C₁-C₆ alkylamino lower alkyl; and

R_(c) is hydrogen or lower alkyl.

More preferred compounds of Formula XXVIII are those where A ismethylene, R_(a) and R_(a)′ are independently phenyl optionallysubstituted with methyl or ethyl, and R_(c) is lower alkyl. Particularlypreferred compounds of Formula XXVII are those where A is methylene,R_(a) is phenyl substituted in the para position with lower alkyl,R_(a)′ is phenyl, and R_(c) is C₁-C₃ alkyl.

wherein

A is C₁-C₆ alkylene;

R_(d) and R_(e) are independently lower alkyl groups.

More preferred compounds of Formula XXIX are those where A is C₂-C₄alkylene. Particularly preferred compounds of Formula XXIX are thosewhere A is C₂-C₄ alkylene, R_(d) is C₁-C₃ alkyl, and R_(e) is C₂-C₄alkyl.

wherein

A is C₁-C₆ alkylene;

R_(d) is lower alkyl; and

R_(f) is a group of the formula:

 where

E is oxygen or nitrogen; and

M is C₁-C₃ alkylene or nitrogen.

More preferred compounds of Formula XXX are those where A is C₁-C₃alkylene. Still more preferred compounds of Formula XXX are those whereA is C₂-C₄ alkylene, R_(d) is C₁-C₃ alkyl, and R_(e) is C₂-C₄ alkyl.Particularly preferred compounds of Formula XXX are those where A isC₂-C₄ alkylene, R_(d) is C₁-C₃ alkyl, R_(e) is C₂-C₄ alkyl, and E isnitrogen and M is methylene, E is oxygen and M is methylene or ethylene,or E and M are both nitrogen.

Other preferred compounds of Formula XXX are those where R_(f) isfuranyl, tetrahydrofuranyl, or imidazolyl.

wherein

A is C₁-C₆ alkylene;

R_(d) is lower alkyl optionally substituted with amino or mono- ordi(C₁-C₆)alkylamino; and

R_(a)′ is phenyl optionally mono-, di-, or trisubstituted with halogen,lower alkyl, lower alkoxy, or mono- or di-C₁-C₆ alkylamino, or mono- ordi-C₁-C₆ alkylamino lower alkyl.

More preferred compounds of Formula XXXI are those where A is C₁-C₃alkylene, R_(a)′ is phenyl optionally substituted with methyl or ethyl,and R_(d) is C₁-C₃ alkyl. Still more preferred compounds of Formula XXXIare where A is methylene, R_(a)′ is phenyl optionally substituted withmethyl or ethyl, and R_(d) is C₃-C₆ alkyl. Particularly preferredcompounds of Formula XXXI are sodium, potassium, or ammonium salts ofthe corresponding parent compound.

Other preferred compounds of Formula XXXI are those where R_(a)′ isphenyl substituted with mono- or di-(C₁-C₆)alkylamino lower alkyl.

wherein

A is C₁-C₆ alkylene;

R_(d) is lower alkyl; and

R_(a)″ is phenyl, pyridyl, imidazolyl, pyrimidinyl, or pyrrolyl, each ofwhich is optionally substituted with up to two groups selected fromhalogen, lower alkyl, lower alkoxy, mono- or di(C₁-C₆)alkylamino, ormono- or di-C₁-C₆ alkylamino lower alkyl.

More preferred compounds of Formula XXXIa are those where R_(a)″ isimidazolyl and R_(d) is C₁-C₃ alkyl. Still more preferred compounds ofFormula XXXI are where A is methylene, R_(a)″ is imidazolyl, and R_(d)is C₃-C₆ alkyl.

wherein

A is C₁-C₆ alkylene; and

R_(d) and R_(e) are independently lower alkyl groups.

More preferred compounds of Formula XXXII are those where A is C₁-C₃alkylene. Particularly preferred compounds of Formula XXXII are thosewhere A is C₁-C₃ alkylene, R_(d) is C₁-C₃ alkyl, and R_(e) is C₁-C₃alkyl.

wherein

D is nitrogen or CH;

D′ is nitrogen or oxygen;

A is C₁-C₆ alkylene; and

R_(a)′ is phenyl, pyridyl, or thiazolyl, each of which is optionallymono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy,or mono- or di-C₁-C₆ alkylamino, or mono- or di-C₁-C₆ alkylamino loweralkyl.

More preferred compounds of Formula XXXIII are those where A is C₁-C₃alkylene, R_(a)′ is phenyl optionally substituted with lower alkyl orhalogen, and D is nitrogen. Still more preferred compounds of FormulaXXXIII are where A is methylene, R_(a)′ is phenyl optionally substitutedwith lower alkyl or halogen, D is nitrogen, and D′ is oxygen.

wherein

A is C₁-C₆ alkylene; and

R_(a)′ is hydrogen;

R_(a)′ is thienyl or phenyl, each of which is optionally mono-, di-, ortrisubstituted with halogen, lower alkyl, lower alkoxy, or mono- ordi-C₁-C₆ alkylamino, or mono- or di-C₁-C₆ alkylamino lower alkyl.

More preferred compounds of Formula XXXIV are those where A is C₁-C₃alkylene, and R_(a)′ is phenyl optionally substituted with lower alkylor halogen. Still more preferred compounds of Formula XXXIV are where Ais methylene, R_(a)′ is phenyl optionally substituted with lower alkyl,lower alkoxy or halogen.

wherein

A is C₁-C₆ alkylene; and

R_(d) is lower alkyl;

A′ represents oxygen or methylene; and

r is an integer of from 1-3.

More preferred compounds of Formula XXXV are those where A is C₁-C₃alkylene. Particularly preferred compounds of Formula XXXV are thosewhere A is C₁-C₃ alkylene, and R_(d) is C₁-C₃ alkyl.

wherein

A is C₁-C₆ alkylene; and

R_(h) and R_(h)′ are independently hydrogen or lower alkyl, where eachalkyl is optionally substituted with lower alkoxy;

A′ represents oxygen or methylene; and

r is an integer of from 1-3.

More preferred compounds of Formula XXXVa are those where A is C₁-C₃alkylene. Particularly preferred compounds of Formula XXXV are thosewhere A is C₁-C₃ alkylene, and R_(h) is C₁-C₃ alkyl.

wherein

A is C₁-C₆ alkylene;

R_(g) is lower alkoxy lower alkyl; and

R_(a)′ is phenyl optionally mono-, di-, or trisubstituted with halogen,lower alkyl, lower alkoxy, or mono- or di-C₁-C₆ alkylamino, or mono- ordi-C₁-C₆ alkylamino lower alkyl.

wherein

R_(j) is halogen or lower alkoxy; and

R_(k) is lower alkyl or cycloalkyl each of which is optionallysubstituted with hydroxy, lower alkyl, or lower alkoxy; or

R_(k) is phenyl (C₁-C₆) alkyl where the phenyl group is optionallymono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy,or mono- or di-C₁-C₆ alkylamino, or mono- or di-C₁-C₆ alkylamino loweralkyl.

wherein

A is C₁-C₆ alkylene;

R_(l) is lower alkoxy, benzyloxy, lower alkoxy lower alkoxy, amino, ormono- or di-(C₁-C₆)alkylamino; and

R_(m) is pyranyl, dihydropyranyl, tetrahydropyranyl, orhexahydropyranyl, pyridine, dihydropyridine, tetrahydropyridine, orpiperidine.

Preferred compounds of Formula XXXVIII are those where R_(l) is loweralkoxy and R_(m) is tetrahydropyranyl.

wherein

A is C₁-C₆ alkylene;

R_(n) is lower alkoxy, lower alkoxy lower alkoxy, benzyl, or a group ofthe formula:

 where

D is nitrogen or CH; and

D′ is nitrogen or oxygen; and

R_(o) is pyranyl, 2- or 3-thienyl; or

R_(o) is 2-, 4-, or 5-thiazolyl or 2-, 4-, or 5-imidazolyl, each ofwhich may be optionally substituted with lower alkyl.

Preferred compounds of Formula XXXIX are those where

wherein

A is C₁-C₆ alkylene;

R_(h) and R_(h)′ are independently hydrogen or lower alkyl, where eachlower alkyl is optinally substituted with lower alkoxy; and

R_(a)′ is phenyl optionally mono-, di-, or trisubstituted with halogen,lower alkyl, lower alkoxy, or mono- or di-C₁-C₆ alkylamino, or mono- ordi-C₁-C₆ alkylamino lower alkyl; or

R_(a)′ is thienyl optionally substituted with lower alkyl.

wherein

A is C₁-C₆ alkylene;

D is nitrogen or CH;

D′ is nitrogen or oxygen; and

R_(p) is lower alkyl or lower alkyl optionally substituted with loweralkoxy.

wherein

A is C₁-C₆ alkylene;

X is defined as above for Formula I; and

R₁₈ is

(i) amino or mono- or di(C₁-C₆)alkylamino; or

(ii) lower alkyl optionally substituted with

 where

V and V′ are independently CH or nitrogen;

A″ is C₁-C₆ alkylene; and

R₂₀ is phenyl, pyridyl, or pyrimidinyl, each of which is optionallymono-, di-, or trisubstituted independently with halogen, hydroxy, C₁-C₆alkoxy, amino, or mono- or di(C₁-C₆)alkylamino.

More preferred compounds of Formula XXXXII are those where V is nitrogenand X is C₁-C₆ alkoxy or C₁-C₆ alkyl optionally substituted with up tothree halogen atoms. Particularly preferred compounds of XXXXII arethose where V and V′ are nitrogen; X is C₁-C₃ alkoxy or C₁-C₃ alkyloptionally substituted with up to three halogen atoms; A″ is methyleneor ethylene; and R₂₀ is halogenated phenyl. A preferred R₂₀ group is4-fluorophenyl. Highly preferred compounds of XXXXII are those where Xis 2,2,2-trifluoroethyl; V and V′ are nitrogen; R₂₀ is halogenatedphenyl; and A and A′ are methylene or ethylene.

In certain situations, compounds of Formula I may contain one or moreasymmetric carbon atoms, so that the compounds can exist in differentstereoisomeric forms. These compounds can be, for example, racemates oroptically active forms. In these situations, the single enantiomers,i.e., optically active forms, can be obtained by asymmetric synthesis orby resolution of the racemates. Resolution of the racemates can beaccomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral HPLC column.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Table Iand their pharmaceutically acceptable acid and base addition salts. Inaddition, if the compound of the invention is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)n-ACOOH where nis 0-4, and the like. Non-toxic pharmaceutical base addition saltsinclude salts of bases such as sodium, potassium, calcium, ammonium, andthe like. Those skilled in the art will recognize a wide variety ofnon-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

By lower alkyl in the present invention is meant straight or branchedchain alkyl groups having 1-6 carbon atoms, such as, for example,methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl.

By cycloalkyl in the present invention is meant cycloalkyl groups having3-7 atoms such as, for example cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl.

By aryl is meant an aromatic carbocyclic group having a single ring(e.g., phenyl), multiple rings (e.g., biphenyl) or multiple condensedrings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which isoptionally mono-, di-, or trisubstituted with, e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy.

By lower alkoxy in the present invention is meant straight or branchedchain alkoxy groups having 1-6 carbon atoms, such as, for example,methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy,pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy,and 3-methylpentoxy. By cycloalkoxy in the present invention is meantcycloalkylalkoxy groups having 3-7 carbon atoms where cycloalkyl isdefined above.

By halogen in the present invention is meant fluorine, bromine,chlorine, and iodine.

By heteroaryl (aromatic heterocycle) in the present invention is meantone or more aromatic ring systems of 5-, 6-, or 7-membered ringscontaining at least one and up to four hetero atoms selected fromnitrogen, oxygen, or sulfur. Such heteroaryl groups include, forexample, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl,pyrimidinyl, (iso)quinolinyl, naphthyridinyl, benzimidazolyl, andbenzoxazolyl.

Specific examples of heteroaryl groups are the following:

wherein

Q is nitrogen or —CR₉;

T is —NR₇, oxygen, or sulfur; and

R₉, R₁₀, R₁₀′, R₁₁, R₁₁′, R₁₂ are as defined above.

Where Y represents a carbocyclic group, it is attached to the amidenitrogen by a single bond. The result is an amide of the formula:

where X is defined as above and

represents the Y carbocyclic group.

Where X is a carbocyclic group, such moiety or group includes botharomatic heterocycles (heteroaryl), unsaturated heterocylic ringsystems, and saturated heterocyclic ring systems. Examples of suchgroups are imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, orpiperidinyl. Preferred X carbocyclic groups are linked to the parentnaphthyridine moiety by a nitrogen atom in the X carbocyclic group.Thus, for example, when pyrrolidinyl is the X carbocyclic group, it ispreferably a 1-pyrrolidinyl group of the formula:

Where Y is a carbocyclic group, such moiety or group includes botharomatic heterocycles (heteroaryl groups), unsaturated heterocylic ringsystems, and saturated heterocyclic ring systems. Examples of suchgroups are imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, orpiperidinyl. Preferred Y carbocyclic groups are linked to the parentnaphthyridine carboxamide group by a nitrogen atom in the Y carbocyclicgroup. Thus, for example, when piperidinyl is the Y carbocyclic group,it is preferably a 1-piperidinyl group of the formula:

By “optionally substituted phenyl” as used herein is meant phenyl groupsthat are unsubstituted or substituted with up to 3 groups selectedindependently from halogen, hydroxy, lower alkyl, lower alkoxy,trifluoromethyl, and mono- or di-lower alkylamino.

Representative compounds of the invention are shown below in Table 1.

TABLE 1

Compound 1

Compound 2

Compound 3

Compound 4

Compound 5

Compound 6

Compound 7

Compound 8

Compound 9

Compound 10

The pharmaceutical utility of compounds of this invention is indicatedby the following assays for GABAa receptor activity.

Assays are carried out as described in Thomas and Tallman (J. Bio. Chem.156: 9838-9842, J. Neurosci. 3: 433-440, 1983). Rat cortical tissue isdissected and homogenized in 25 volumes (w/v) of 0.05 M Tris HCl buffer(pH 7.4 at 4° C.). The tissue homogenate is centrifuged in the cold (4°)at 20,000×g for 20′. The supernatant is decanted and the pellet isrehomogenized in the same volume of buffer and again centrifuged at20,000×g. The supernatant is decanted and the pellet is frozen at −20°C. overnight. The pellet is then thawed and rehomogenized in 25 volume(original wt/vol) of buffer and the procedure is carried out twice. Thepellet is finally resuspended in 50 volumes (w/vol of 0.05 M Tris HClbuffer (pH 7.4 at 40° C.)

Incubations contain 100 ml of tissue homogenate, 100 ml of radioligand0.5 nM (³H-Ro15-1788 [³H-Flumazenil] specific activity 80 Ci/mmol), drugor blocker and buffer to a total volume of 500 ml. Incubations arecarried for 30 min at 4° C. then are rapidly filtered through GFBfilters to separate free and bound ligand. Filters are washed twice withfresh 0.05 M Tris HCl buffer (pH 7.4 at 4° C.) and counted in a liquidscintillation counter. 1.0 mM diazepam is added to some tubes todetermine nonspecific binding. Data are collected in triplicatedeterminations, averaged and % inhibition of total specific binding iscalculated. Total Specific Binding=Total−Nonspecific. In some cases, theamounts of unlabeled drugs is varied and total displacement curves ofbinding are carried out. Data are converted to K_(i)'s. Compounds of theinvention when tested in the assay described above have K_(i)'s of lessthan 1 μM.

In addition, the following assay may be used to determine if thecompounds of the invention are agonists, antagonists, or inverseagonists, and, therefore, their specific pharmaceutical utility. Thefollowing assay can be employed to determine specific GABAa receptoractivity.

Assays are carried out as described in White and Gurley (NeuroReport 6:1313-1316, 1995) and White, Gurley, Hartnett, Stirling, and Gregory(Receptors and Channels 3: 1-5, 1995) with modifications. Xenopus Laevisoocytes are enzymatically isolated and injected with non-polyadenylatedcRNA mixed in a ratio of 4:1:4 for human derived α, β, and γ subunits,respectively. For each subunit combination, sufficient message isinjected to result in current amplitudes of >10 nA when 1 μM GABA isapplied.

Electrophysiological recordings are carried out using the two electrodevoltage-clamp technique at a membrane holding potential of −70 mV.

Compounds are evaluated against a GABA concentration that evokes <10% ofthe maximal evokable GABA current. Each oocyte is exposed to increasingconcentrations of compound in order to evaluate a concentration/effectrelationship. Compound efficacy is expressed as a percent-change incurrent amplitude: 100*((Ic/I)−1), where Ic is the GABA evoked currentamplitude observed in the presence of compound and I is the GABA evokedcurrent amplitude observed in the absence of compound.

Specificity of a compound for the Ro15-1788 site is determined followingcompletion of the concentration/effect curve. After washing the oocytesufficiently to remove previously applied compound, the oocyte isexposed to GABA+1 μM Ro15-1788, followed by exposure to GABA+1 μMRo15-1788+compound. Percent change due to addition of compound iscalculated as described above. Any percent change observed in thepresence of Ro15-1788 is subtracted from the percent changes in currentamplitude observed in the absence of 1 μM Ro15-1788. These net valuesare used for the calculation of average efficacy and EC₅₀ values.

To evaluate average efficacy and EC₅₀ values, the concentration/effectdata are averaged across cells and fit to the logistic equation. Averagevalues are reported as mean±standard error.

The substituted 4-oxo-napthyridine-3-carboxamides of Formula I and theirsalts are suitable for the diagnosis and treatment of anxiety, DownSyndrome, sleep, cognitive and seizure disorders, and overdose withbenzodiazepine drugs and for enhancement of alertness, both in human andnon-human animals and domestic pets, especially dogs and cats and farmanimals such as sheep, swine and cattle.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the species of the host animal to be treated, the particular modeof administration, and the body weight of the host. Dosage unit formswill generally contain between from about 1 mg to about 500 mg of anactive ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

For administration to non-human animals, the composition may also beadded to the animal feed or drinking water. It will be convenient toformulate these animal feed and drinking water compositions with amullet-dose of the drug so that the animal takes in an appropriatequantity of the composition along with its diet. It will also beconvenient to present the composition as a premix for addition to thefeed or drinking water.

An illustration of the preparation of compounds of the present inventionis given in Scheme I.

In Scheme I, the substituents X and Y carry the definitions set forthabove for formula I.

Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present inventions, as demonstrated by the followingexamples. In some cases, protection of certain reactive functionalitiesmay be necessary to achieve some of the above transformations. Ingeneral, the need for such protecting groups will be apparent to thoseskilled in the art of organic synthesis as well as the conditionsnecessary to attach and remove such groups.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them.

EXAMPLE 1

Preparation of Starting Materials and Intermediates

The starting materials and various intermediates may be obtained fromcommercial sources, prepared from commercially available organiccompounds, or prepared using well known synthetic methods.

Representative examples of methods for preparing intermediates of theinvention are set forth below.

1. 2-Benzylamino-5-nitropyridine

A solution of 2-chloro-5-nitropyridine (1.59 g, 10 mmol) and benzylamine(2.3 mL, 21 mmol) in ethanol (10 mL) was heated at reflux for 2 h. Thereaction mixture was allowed to ambient temperature, 1.2 N HCl wasadded, the precipitate collected, rinsed with water, and dried to give2.02 g of 2-benzylamino-5-nitropyridine as a yellow solid.

2. 2-Benzylamino-5-aminopyridine

A mixture of 2-benzylamino-5-nitropyridine (2.02 g) and 10% Pd/C (202mg) in ethanol (20 mL) was placed in a Paar bottle and shaken underhydrogen (50 PSI) for 3 h. The mixture was filtered through Celite usingdichloromethane and concentrated in vacuo to afford 1.76 g of2-benzylamino-5-aminopyridine as a burgundy oil.

3. Diethyl(2-benzylamino-5-pyridylaminomethylene)malonate

A mixture of 2-benzylamino-5-aminopyridine (1.76 g) and diethylethoxymethylenemalonate (1.78 mL, 8.82 mmol) was heated at 130° C. for 2h. While warm, the mixture was evacuated. After cooling, the product wastriturated with 2:1 hexanes/ether and collected to give 2.74 g ofdiethyl (2-benzylamino-5-pyridylaminomethylene)malonate as a gold solid.

4. Ethyl 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate

Diethyl(2-benzylamino-5-pyridylaminomethylene)malonate (2.23 g) wasadded to diphenyl ether (10 mL) preheated to 230° C. Heating wascontinued for 0.5 h, the reaction flask removed from the oil bath, andthe mixture allowed to cool to ambient temperature. The product wastriturated with 1:1 ether:hexanes, collected, rinsed with ether, anddried to give 1.47 g of ethyl6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate as abrown solid.

5. 6-Benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic Acid

A mixture of ethyl6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (60 mg),1N NaOH (2 mL), and ethanol (0.5 mL) was heated at reflux for 2 h. Thereaction mixture was cooled in an ice bath and saturated aqueousammonium chloride was added. The resulting precipitate was collected,rinsed with water and ether, then dried to afford 35 mg of6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid as abrown solid.

6. 2-Ethoxy-5-nitropyridine

2-Chloro-5-nitropyridine was added to a homogeneous solution ofpotassium hydroxide (3.93 g, 70 mmol) in ethanol (35 mL) at ambienttemperature. The reaction mixture was stirred for 1 h, then diluted withsaturated aqueous ammonium chloride and cooled in an ice bath. Theprecipitate was collected, rinsed with water and dried to give 3.60 g of2-ethoxy-5-nitropyridine as a beige solid.

7. 2-Ethoxy-5-aminopyridine

A mixture of 2-ethoxy-5-nitropyridine (3.60 g) and 10% Pd/C (360 mg) inethanol (40 mL) was placed in a Paar bottle and shaken under hydrogen(50 PSI) for 16 h. The mixture was filtered through Celite usingdichloromethane and concentrated to give 2.892 g of2-ethoxy-5-aminopyridine as a gold solid.

8. Diethyl(2-ethoxy-5-pyridylaminomethylene)malonate

A mixture of 2-ethoxy-5-aminopyridine (2.89 g, 20.9 mmol) and diethylethoxymethylenemalonate (4.23 mL, 20.9 mmol) was heated at 130° C. for4.5 hours. While warm, the mixture was evacuated. After cooling, theproduct was triturated with 2:1 hexanes:ether and collected to afford6.04 g of diethyl (2-ethoxy-5-pyridylaminomethylene)malonate as a beigesolid.

9. Ethyl 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate

Diethyl(2-ethoxy-5-pyridylaminomethylene)malonate (6.04 g) was added todiphenyl ether (20 mL) preheated to 230° C. Heating was continued for0.5 h, the reaction flask removed from the oil bath, and the mixtureallowed to cool to ambient temperature. The product was triturated with1:1 ether:hexanes, collected, rinsed with ether, and dried to gave 2.98g of ethyl 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate asa tan solid.

10. 6-Ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic Acid

A mixture of ethyl6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (2.98 g), 1NNaOH (50 mL) and ethanol (10 mL) was heated at reflux for 2 h. Thereaction mixture was cooled in an ice bath, acidified, and the resultingprecipitate collected, rinsed with water and dried to give 2.42 g of6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid as abeige solid.

11. 4-[(n-tert-Butoxycarbonyl)-methylaminomethyl)benzylamineHydrochloride

a) A solution of α-bromo-p-tolunitrile (4.90 g, 25 mmol) in acetonitrile(50 mL) was added dropwise to a stirring solution of 40% aqueousmethylamine (21.5 mL, 250 mmol) in acetonitrile (50 mL) at 0° C. Thereaction mixture was stirred 0.5 h, then concentrated in vacuo. Waterwas added to the residue and extracted 2× with dichloromethane. Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo to give 1.41 g of4-(methylaminomethyl)benzonitrile as a yellow oil containing ˜30% ofN,N-bis(4-benzonitrile)methyl-amine. The aqueous was adjusted to pH>8and extracted 2× with 9:1 dichloromethane:methanol. The combinedextracts were dried over sodium sulfate, filtered, and concentrated invacuo to give 1.13 g of pure 4-(methylamino)benzonitrile as a colorlessoil.

b) Di-tert-butyl dicarbonate (1.77 g, 8.1 mmol) was added to a stirringmixture of 4-(methylaminomethyl)-benzonitrile (1.13 g, 7.7 mmol) and 1NNaOH (15 mL) in 1,4-dioxane (15 mL) at ambient temperature. The reactionmixture was stirred for 2 h, poured into saturated aqueous sodiumchloride, and extracted with dichloromethane. The organic layer wasdried over sodium sulfate, filtered, and concentrated in vacuo to give1.81 g of crude4-{N-(tert-butoxycarbonyl)-methylaminomethyl]benzonitrile. The crudematerial was filtered through a 1″ silica gel pad, first eluting withhexane, then with ether. The ether filtrate was concentrated to givepure 4-{N-(tert-butoxycarbonyl)-methylaminomethyl]benzonitrile as acolorless oil. To this was added 10% Pd/C (170 mg) and ethanol in a Paarbottle. The mixture was shaken under hydrogen (50 PSI) for 4.5 h, thenfiltered through Celite and concentrated in vacuo. The residue was takenup in ethanol, cooled in an ice bath, and 1.0 M HCl in ether (10 mL) wasadded dropwise. The resulting precipitate was filtered and dried in avacuum oven to give 1.346 g of4-[(N-tert-butoxycarbonyl)-methylaminomethyl)-benzylamine hydrochlorideas a pale gray solid.

EXAMPLE 2

1.N-n-Butyl-6-benzylamino-4-oxo-4-dihydro-1,5-naphthyridine-3-carboxamide

To a solution of6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (53mg, 0.2 mmol) and triethylamine (59 ml, 0.42 mmol) inN,N-dimethylformamide (1 mL) at 0° C. was added ethyl chloroformate (39mL, 0.41 mmol). After stirring at 0° C. for 1 h, n-butylamine 99 mL, 1.0mmol) was added. The reaction mixture was stirred an additional 2 h at0° C., then poured into saturated aqueous sodium chloride. The mixturewas cooled in an ice bath, the precipitate collected, rinsed with waterand ether, then dried to afford 49 mg of N-n-butyl6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide as abrown solid. Compound 1. An alternate name for this compound is:N-butyl(4-oxo-6-(benzylamino)(3-hydro-5-azaquinolyl))formamide.

2. N-[2-(Ethylthio)ethyl]6-methoxy-4-oxo-1,4-dihydro-1,5-napththyridine-3-carboxamide

To a solution of6-methoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (55 mg,0.25 mmol) and triethylamine (73 mL, 0.53 mmol) in N,N-dimethylformamide(2 mL) at 0° C. was added ethyl chloroformate (49 mL, 0.52 mmol). Afterstirring at 0° C. for 0.5 h, 2-(ethylthio)ethylamine hydrochloride (172mg, 1 mmol) and triethylamine (139 ml, 1 mmol) was added. The reactionmixture was stirred for 0.5 h at 0° C., then poured into 1.2 N HCl,cooled in an ice bath, and the resulting precipitate collected, rinsedwith water and dried to give 57 mg of N-[2-(ethylthio)ethyl]6-methoxy-4-oxo-1,4-dihydro-1,5-napththyridine-3-carboxamide as a beigesolid; m.p. 257-259° C. (d). Compound 5.

3. N-[4-(Methylaminomethyl)benzyl]6-(2-methoxyethoxy)-4-oxo-1,4-dihydro-1,5 naphthyridine-3-carboxamideHydrochloride

To a solution of6-(2-methoxyethoxy)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylicacid (106 mg, 0.4 mmol) and triethylamine (117 mL, 0.84 mmol) in 4:1tetrahydrofuran: N,N-dimethylformamide (2 mL) at 0° C. was added ethylchloroformate (66 mL, 0.82 mmol). After stirring at 0° C. for 1.25 h,4-[(N-tert-butoxycarbonyl)-methylaminomethyl)benzylamine hydrochloride(120 mg, 0.42 mmol) and triethylamine (59 mL, 0.42 mmol) was added. Thereaction mixture was stirred at 0° C. for 0.75 h, then allowed toambient temperature and stirred for 20 h. N,N-Dimethylethylenediamine(132 mL, 1.2 mmol) was added, the reaction mixture stirred for 1 h, thenconcentrated in vacuo. The residue was cooled in an ice bath, saturatedaqueous ammonium chloride was added and the mixture extracted withdichloromethane. The organic layer was washed with saturated aqueoussodium chloride, dried over sodium sulfate, filtered, and concentratedto give 177 mg of crude N-[4-(N-tertbutoxycarbonyl)-methylaminomethyl)benzyl]6-(2-methoxyethoxy)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide.

To crudeN-[4-(N-tert-butoxycarbonyl)-methylaminomethyl)benzyl]6-(2-methoxyethoxy)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamidein dichlorometnane (1 mL) was added 1:1 trifluoroaceticacid:dichloromethane (2 mL dropwise at ambient temperature. The reactionmixture was stirred for one hour, concentrated in vacuo, the residuedissolved in ethanol, and 1.0M HCl in ether (0.8 mL) was added. Theprecipitate was collected to afford 68 mg ofN-[4-(methylaminomethyl)benzyl]6-(2-methoxyethoxy)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamidehydrochloride. Compound 10.

4. N-(4-Methoxybenzyl)6-pyrrolidino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide

To a solution of6-pyrrolidino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (80mg, 0.3 mmol) and triethylamine (0.11 mL, 0.8 mmol) in 5:1tetrahydrofuran: N,N-dimethylformamide (6 mL) at 0° C. was added ethylchloroformate (0.09 mL, 0.9 mmol). After stirring at 0° C. for 0.5 h,4-methoxybenzylamine (0.1 mL, 0.8 mmol) was added. The reaction mixturewas allowed to ambient temperature and stirred for 0.5 h. Water wasadded and the resulting precipitate collected, washed with water andether and dried. The solid was combined with 1N NaOH (5 mL) and ethanol(2 mL) and heated at reflux for 0.25 h. The reaction mixture was cooledin an ice bath, 3N HCl was added to achieve pH 8, and the precipitatecollected, rinsed with water and ether and dried to give 69 mg ofN-(4-methoxybenzyl)6-pyrrolidino-4-oxo-1,4-dihydro-1,5-naphthyri-dine-3-carboxamide; m.p.270-272 C. Compound 8.

5a. N-Benzyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-napthyridine-3-carboxamide, SodiumSalt

N-Benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-napthyridine-3-carboxamide(914 mg, 2.83 mmol) is suspended in ethyl alcohol (9 mL) and 10 N NaOH(0.27 mL) is added. The mixture is heated until homogenous, subsequentlycooled and concentrated. The resulting solid is treated with ethylacetate (5 mL) and ethyl alcohol (250 mL), and the resulting mixture isstirred for 22 h. The precipitate is collected, rinsed with ethylacetate and dried to give the sodium salt of N-benzyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-napthyridine-3-carboxamide (Compound12) (960 mg) as a tan solid.

5b. N-benzyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-napthyridine-3-carboxamide, PotassiumSalt; (Compound 13) m.p. 286-288° C.

EXAMPLE 3

The following compounds were prepared essentially according to theprocedures described in Examples 1-2:

(a) N-n-Butyl6-chloro-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound14) m.p. 330° C. (d).

(b) N-Propan-3-ol6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 15) m.p. 271-272° C.

(c) N-n-Butyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound16) m.p. 274-276° C.

(d) N-(2-Ethylthio)ethyl6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 17) m.p. 257-259° C.

(e) N-n-Butyl6-(N-benzylamino)-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide(Compound 18).

(f) N-n-Pentyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound19) m.p.265-265° C.

(g) N-(3-Isopropoxy)propyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound20).

(h) N-Benzyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound21) m.p.275-278° C.

(i) N-2-Pentyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound22).

(j) N-(2-Tetrahydrofuranyl)methyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;m.p.235-237° C. (Compound 4).

(k) N-(3-Methoxy)propan-2-ol6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound23).

(l) N-(3-Methoxy)propyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound24).

(m) N-(2-Methoxy)ethyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound25).

(n) N-Isoamyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound26) m.p. 279-281° C.

(o) N-(2-Furanyl)methyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound27) m.p. 245 (d)° C.

(p) N-(3-Methoxybenzyl)6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; m.p.250-253° C. (Compound 11).

(q) N-(3-Ethoxy)propyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound28) m.p. 224-225° C.

(r) N-2-(2-Methyl)butyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; Compound29) m.p. 282-283° C.

(s) N-2-Pentan-1-ol6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound30) m.p. 232-234° C.

(t) N-5-Pentanol6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound31) m.p. 223-224° C.

(u) N-1-Cyclohexan-2-ol6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound32) m.p.268-270° C.

(v) N-Benzyl6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 33) m.p. 273-274° C.

(w) N-(2-Fluorobenzyl)6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 34) m.p. 266-271° C.

(x) N-(3-Fluorobenzyl)6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 35) m.p.281° C.

(y) N-(4-Fluorobenzyl)6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 36) m.p.283-286° C.

(z) N-(Imidazol-4-ylmethyl)6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. (Compound6).

[Alternate Name:(6-ethoxy-4-oxo(3-hydro-5-azaquinolyl))-N-(imidazol-4-ylmethyl)formamide]

(aa) N-4-Tetrahydropyranyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound37) m.p.303-305° C.

(bb) N-(3-Thienyl)methyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound38) m.p.324-325° C.

(cc) N-2-(6-Methyl)heptan-6-ol6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound39) m.p.281° C.

(dd) N-(2-Tetrahydropyranyl)methyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound40) m.p.204-206° C.

(ee) N-(2-Fluorobenzyl)6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound41) m.p. 157-162° C.

(ff) N-(3-Fluorobenzyl)6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound42) m.p. 297-302° C.

(gg) N-(4-Fluorobenzyl)6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound43).

(hh) N-(4-Methoxybenzyl)6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound44) m.p.186° C.

(ii) N-(3-Fluorobenzyl)6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 45) m.p.301° C.

(jj) N-Benzyl6-(N-methyl,N-toluenesulfonyl-amino)-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide.(Compound 2). [Alternate name:(6-(methyl((4-methylphenyl)sulfonyl)amino)-4-oxo(3-hydro-5-azaquinolyl))-N-benzylformamide]

(kk) N-Benzyl6-(methylamino)-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide(Compound 46).

(ll) N-Piperonyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; m.p.190°C. (Compound 9).

(mm) N-Piperonyl6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 47) m.p.186° C.

(nn) N-2-(Imidazol-4-ylethyl)6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound48) m.p.268° C.

(oo) N-(4-Methylbenzyl)6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound49) m.p.270-271° C.

(pp) N-Benzyl6-(2-methoxyethoxy)-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 50) m.p.>300° C.

(qq) N-Benzyl6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 51) m.p.246-249° C.

(rr) N-Isoamyl6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 52) m.p.295-298° C.

(ss) N-Benzyl6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 53) m.p. 88-90° C.

(tt) N-(2-Fluorobenzyl)6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;m.p.137-139° C. 9 Compound 7).

(uu) N-(3-Ethoxy)propyl6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 54) m.p.150-152° C.

(vv) N-n-Butyl6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 55) m.p.275-277° C.

(ww) N-(2-Pyridyl)methyl6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 56) m.p.125-127° C.

(xx) N-(2-Thienyl)methyl6-(2-methoxyethoxy)-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 57) m.p.235-236° C.

(yy) N-Isoamyl6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 58) m.p. 254-256° C.

(zz) N-(2-Thienyl)methyl6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 59) m.p.277-279° C.

(aaa) N-(2-Thienyl)methyl6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 60) m.p. 240° C.

(bbb) N-(2-Thiazolyl)methyl6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 61) m.p.270-272° C.

(ccc) N-(4-Methylaminomethyl)benzyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound62).

(ddd) N-[4-(1-Methylamino)ethyl]benzy6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound63) m.p. 259-262° C.

(eee) N-(2-Tetrahydrofuranyl)methyl6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 64) m.p. 285-288° C.

(fff) N-n-Pentyl6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 65) m.p.278-280° C.

(ggg) N-(3-Methoxybenzyl)6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 66) m.p.204-205° C.

(hhh) N-(3-Fluorobenzyl)6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 67) m.p.263-265° C.

(iii) N-(4-Methylaminomethyl)benzyl6-(2-methoxyethoxy)-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 68) m.p. 275-277° C.

(jjj) N-n-Butyl6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 69) m.p.57-58° C.

(kkk) N-(4-Methoxybenzyl)6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 70) m.p.270-272° C.

(lll) N-(2-Thienyl)methyl6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 71) m.p.265-267° C.

(mmm) N-[4-(1-Methylamino)ethyl]benzyl6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide(Compound 72).

(nnn) N-(4-Methylaminomethyl)benzyl6-n-propoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamidehydrochloride; (Compound 73) m.p.270-271° C.

(ooo) N-[4-(1-Methylamino)ethyl]benzyl6-chloro-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound74) m.p.260-263° C.

(ppp) N-[4-(1-Methylamino)ethyl]benzyl6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamidehydrochloride; (Compound 75) m.p.298-302° C.

(qqq) N-(4-Ethoxybenzyl)6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 76) m.p.278-281° C.

(rrr) N-(4-Ethoxybenzyl)6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 77) m.p.265-267° C.

(sss) N-(4-Chlorobenzyl)6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 78) m.p.295-297° C.

(ttt) N-(3-Chlorobenzyl)6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 79) m.p.276-278° C.

(uuu) N-Piperonyl6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamidehydrochloride; (Compound 80) m.p.246-247° C.

(vvv) N-Benzyl6-(2-methylamino)ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide(Compound 81).

(www) N-Benzyl6-(2-dimethylamino)ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 82) m.p.194-198° C.

(xxx) N-(4-Ethylaminomethyl)benzyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound83) m.p.194° C (d).

(yyy) N-Benzyl6-(2-methoxy)ethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 84) m.p.254-257° C.

(zzz) N-(3-Methylaminomethyl)benzyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamidehydrochloride; (Compound 85) m.p.187° C. (d).

(aaaa) N-(4-Dimethylaminomethyl)benzyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamidehydrochloride; (Compound 86) m.p.200° C. (d).

(bbbb) N-(3-Methylaminomethyl)benzyl6-n-propoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridlne-3-carboxamidehydrochloride; (Compound 87) m.p.184° C. (d).

(cccc) N-[4-(1-Imidazolylmethy)]benzyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound88) m.p. 143-145° C.

(dddd) N-[4-(1-morpholinomethyl)]benzyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-napthyridine-3-carboxamide; (Compound89) m.p. 215-218° C.

(eeee) N-[3-(1-morpholinomethyl)]benzyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-napthyridine-3-carboxamide; (Compound90) m.p. 195-198° C.

(ffff) N-{4-[1-(4-methylpiperazinomethyl)]benzyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-napthyridine-3-carboxamide (Compound91).

(ggggg) N-[4-(1,2,4-triazol-1-ylmethyl)]benzyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-napthyridine-3-carboxamide; (Compound92) m.p.195-200° C.

(hhhh) N-Benzyl6-benzylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide(Compound 93).

(iiii) N-Cyclohexyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound94).

(jjjj) N-Cyclohexylmethyl6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound95).

(kkkk)N-(4-Aminobenzyl)-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide(Compound 96).

(llll) N-(4-Pyridylmethyl)6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound97).

(mmmm) N-Benzyl6-tetrahydrolsoquinolinyl-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide(Compound 98).

(nnnn) N-{4-[1-[4-(4-Fluorobenzyl)piperazinyl]methyl]benzyl}6-(2,2,2-trifluoroethyl)-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide,(Compound 99) m.p. 234-236° C.

(oooo) N-(3-isopropoxypropyl)6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide Compound 3[alternative name:(6-ethoxy-4-oxohydropyridino[3,2-b]pyridin-3-yl)-N-[3-(methylethoxy)propyl]carboxamide].

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula:

or a Pharmaceutically acceptable salt thereof wherein: X is (i)hydrogen, halogen, mono- or dialkylamino, alkoxy, (ii) a group of theformula:

where G is lower alkylene having 1-6 carbon atoms, or a cyclic group ofthe formula

where n is 0, 1, or 2, and m is an integer of from 1 to 5, with theproviso that the sum of n+m is not less than 1 or greater than 5; and R₁is hydrogen, lower alkyl, or (C₃-C₇)cycloalkyl, where the alkyl orcycloalkyl is optionally substituted with halogen, lower alkoxy, ormono- or di (C₁-C₆) alkylamino; (iii) a group of the formula:

where C is as defined for ii; and R₂ and R₃ independently representhydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7carbon atoms, —SO₂R₈ where R₈ is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, oroptionally substituted phenyl, or R₂ and R₃ together with the nitrogenatom to which they are attached form a heterocyclic moiety such asimidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl; (iv)a group of the formula:

where R₂ is as defined for iii; R₄ is hydrogen, lower alkyl having 1-6carbon atoms, or cycloalkyl having 3-7 carbon atoms, and may beoptionally substituted with one or more (C₁-C₆)alkoxy or mono-ordi(C₁-C₆)alkylamino groups; and G is as defined for ii; (v) a group ofthe formula:

where R₂ and G are as defined for iv and ii, respectively, and R₅ and R₆independently represent hydrogen, lower alkyl having 1-6 carbon atoms,cycloalkyl having 3-7 carbon atoms, —SO₂R₈ where R₈ is (C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, or optionally substituted phenyl, or R₅ and R₆together with the nitrogen atom to which they are attached form aheterocyclic moiety; (vi) a group of the formula:

where G is as defined for ii; or (vii) a group of the formula:

where each G is as defined above for ii; and Y is (viii) pyrimidinyl(C₁-C₆alkyl) or pyridyl (C₁-C₅) alkyl; or (ix) a group of the formula:

where is R₁₈ hydrogen, amino, mono-, or di(C₁-C₆)alkylamino, or C₁-C₆alkyl optionally substituted with R₁₉ where R₁₉ represents:

where V and V′ are independently CH or nitrogen; A″ is C₁-C₆ alkylene;and R₂₀ is phenyl, pyridyl, or pyrimidinyl, each of which is optionallymono-, di-, or tri-substituted independently with halogen, hydroxy,C₁-C₆alkoxy, amino, and mono- and di(C₁-C₆) alkylamino.
 2. A compoundaccording to claim 1 wherein Y is 2-pyrimidinylmethyl,4-pyrimdinylmethyl, 2-pyridylethyl, or 4-pyridylmethyl.
 3. A compoundaccording to claim 1 wherein Y is a group of the formula:

where R₁₈ is piperazin-1-ylmethyl or piperidin-1-ylmethyl, each of whichis substituted at the 4-position with a halogenated benzyl group.
 4. Acompound according to claim 1 wherein Y is4-[1-[4-(4-Fluorobenzyl)piperazinyl]methyl]benzyl or4-[1-[4-(4-Fluorobenzyl)piperidinyl]methyl]benzyl.
 5. A compound of theFormula:

or a pharmaceutically acceptable salt thereof wherein: X is a group ofthe formula:

 and Y is (i) lower alkyl having 1-8 carbon atoms or cycloalkyl having3-7 carbon atoms, any of which may be optionally substituted with one ormore halogen, (C₁-C₆)alkoxy, alkoxyalkoxy where each alkoxy is(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₃-C₇)cycloalkylthio, aryl,heteroaryl, or mono- or di(C₁-C₆) alkylamino groups; (ii) a group of theformula:

where K is lower alkylene having 1-6 carbon atoms optionally substitutedwith (C₁-C₆)alkyl or alkylene, or a cyclic group of the formula

where K′ independently represents hydrogen or (C₁-C₆)alkyl or alkylene,n is 0, 1, or 2, and m is an integer of from 1 to 5, with the provisothat the sum of n+m is not less than 1 or greater than 5; and R₉ ishydrogen, lower alkyl, or (C₃-C₇)cycloalkyl, where the alkyl orcycloalkyl is optionally substituted with halogen, lower alkoxy, ormono- or dialkylamino; (iii)a group of the formula:

where K is defined as in ii; (iv) a group of the formula:

where K is as defined for ii, and R₁₃ is hydrogen, lower alkyl having1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, where the alkyland cycloalkyl groups are optionally substituted with one or more(C₁-C₆)alkoxy or mono- or di(C₁-C₆) alkylamino groups; and (v) a groupof the formula:

where K is as defined for ii, and R₇ is hydrogen, lower alkyl having 1-6carbon atoms, or cycloalkyl having 3-7 carbon atoms; and (vi) a group ofthe formula:

where K is as defined for ii; and R₁₄ and R₁₅ independently representhydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7carbon atoms, —SO₂R₈ where R₈ is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, oroptionally substituted phenyl, or R₁₄ and R₁₅ together with the nitrogenatom to which they are attached form a heterocyclic moiety; (vii) agroup of the formula:

where K and R₁₅ are as defined above in ii and vi, respectively; (viii)a group of the formula:

where K is as defined for ii; R₁₀ and R₁₀′ are the same or different andare selected from hydrogen, halogen, hydroxy, lower alkoxy having 1-6carbon atoms, or cycloalkoxy having 3-7 carbon atoms; R₁₁, R₁₁′, and R₁₂are the same or different and are selected from hydrogen, halogen,hydroxy, and —OR₄,—CR₇(R₉)NR₅R₆, —CR₇, (R₁₆)OR₄,  where  R₄ is hydrogen,lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbonatoms, and may be optionally substituted with one or more (C₁-C₆)alkoxyor mono- or di(C₁-C₆)alkylamino groups;  R₅ and R₆ independentlyrepresent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkylhaving 3-7 carbon atoms, or —SO₂R₈; or  R₅ and R₆ together with thenitrogen atom to which they are attached form a heterocyclic moiety; and R₉ is hydrogen, lower alkyl, or (C₃-C₇)cycloalkyl, where the alkyl orcycloalkyl is optionally substituted with halogen, lower alkoxy, ormono- or dialkylamino;  R₁₆ is hydrogen, lower alkyl having 1-6 carbonatoms,  or cycloalkyl having 3-7 carbon atoms; or  R₁₁ and R₁₂ takentogether with the atoms to which they are attached form a (hetero)cyclicring; (ix) a group of the formula:

where K is as defined above for ii; and W is heteroaryl; (x) a group ofthe formula:

where K is as defined for ii; R₁₀ and R₁₁ are as defined for viii, andR₁₇ is hydrogen, lower alkyl, or (C₃-C₇)cycloalkyl, where the alkyl orcycloalkyl is optionally substituted with halogen, lower alkoxy, ormono- or di(C₁-C₆)alkylamino; (xi) a group of the formula:

where K, R₁₀, R₁₂, and R₁₇ are as defined above; (xii) a group of theformula:

where each K is as defined as for ii and R₁₀ is defined above; (xii-1) agroup of the formula:

where K, R₁₀, R₁₁, R₁₄, and R₁₅ are as defined above; and (xiii) a groupof the formula:

where K, R₁₀, R₁₂, R₁₄, and R₁₅ are as defined above; (xiv) pyrimidinyl(C₁-C₆alkyl) or pyridyl (C₁-C₅)alkyl; or (xv) a group of the formula:

where R₁₈ is hydrogen, amino, mono-, or di(C₁-C₆)alkylamino, or C₁-C₆alkyl optionally substituted with R₁₉ where R₁₉ represents:

where V and V′ are independently CH or nitrogen; A″ is C₁-C₆ alkylene;and R₂₀ is phenyl, pyridyl, or pyrimidinyl, each of which is optionallymono-, di-, or tri-substituted independently with halogen, hydroxy,C₁-C₆alkoxy, amino, and mono- and di (C₁-C₆) alkylamino.
 6. A compoundof the formula:

or a Pharmaceutically acceptable salt thereof, wherein R₁ is hydrogen,lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbonatoms, where each alkyl may be optionally substituted with —OR₄ or—NR₅R₆; R₄ is hydrogen, lower alkyl having 1-6 carbon atoms, orcycloalkyl having 3-7 carbon atoms, and may be optionally substitutedwith one or more (C₁-C₆)alkoxy or mono- or di (C₁-C₆) alkylamino groups;R₅ and R₆ independently represent hydrogen, lower alkyl having 1-6carbon atoms, cycloalkyl having 3-7 carbon atoms, or —SO₂R₈, where R₈ is(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl or optionally substituted phenyl; or R₅and R₆ together with the nitrogen atom to which they are attached form aheterocyclic moiety; Y is (i) lower alkyl having 1-8 carbon atoms orcycloalkyl having 3-7 carbon atoms, any of which may be optionallysubstituted with one or more halogen, (C₁-C₆)alkoxy, alkoxyalkoxy whereeach alkoxy is (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₃-C₇)cycloalkylthio,aryl, heteroaryl, or mono- or di(C₁-C₆) alkylamino groups; (ii) a groupof the formula:

where K is lower alkylene having 1-6 carbon atoms optionally substitutedwith (C₁-C₆)alkyl or alkylene, or a cyclic group of the formula

where K′ independently represents hydrogen or (C₁-C₆)alkyl or alkylene,n is 0, 1, or 2, and m is an integer of from 1 to 5, with the provisothat the sum of n+m is not less than 1 or greater than 5; and R₉ ishydrogen, lower alkyl, or (C₃-C₇)cycloalkyl, where the alkyl orcycloalkyl is optionally substituted with halogen, lower alkoxy, ormono- or dialkylamino; (iii) a group of the formula:

where K is defined as in ii; (iv) a group of the formula:

where K is as defined for ii, and R₁₃ is hydrogen, lower alkyl having1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, where the alkyland cycloalkyl groups are optionally substituted with one or more(C₁-C₆)alkoxy or mono- or di(C₁-C₆) alkylamino groups; and (v) a groupof the formula:

where K is as defined for ii, and R₇ is hydrogen, lower alkyl having 1-6carbon atoms, or cycloalkyl having 3-7 carbon atoms; and (vi) a group ofthe formula:

where K is as defined for ii; and R₁₄ and R₁₅ independently representhydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7carbon atoms, —SO₂R₈ where R₈ carries the definition set forth above, orR₁₄ and R₁₅ together with the nitrogen atom to which they are attachedform a heterocyclic moiety; (vii) a group of the formula:

where K and R₁₅ are as defined above in ii and vi, respectively; (viii)a group of the formula:

where K is as defined for ii; R₁₀ and R₁₀′ are the same or different andare selected from hydrogen, halogen, hydroxy, lower alkoxy having 1-6carbon atoms, or cycloalkoxy having 3-7 carbon atoms; R₁₁, R₁₁′, and R₁₂are the same or different and are selected from hydrogen, halogen,hydroxy, and —OR₄, —CR₇(R₉)NR₅R₆, —CR₇(R₁₆)OR₄,  where R₄, R₅, and R₆carry the definitions set forth above; and R₉ is hydrogen, lower alkyl,or (C₃-C₇)cycloalkyl, where the alkyl or cycloalkyl is optionallysubstituted with halogen, lower alkoxy, or mono- or dialkylamino; R₁₆ ishydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7carbon atoms; or R₁₁ and R₁₂ taken together with the atoms to which theyare attached form a (hetero)cyclic ring; (ix) a group of the formula:

where K is as defined above for ii; and W is heteroaryl; (x) a group ofthe formula:

where K is as defined for ii; R₁₀ and R₁₁ are as defined for viii, andR₁₇ is hydrogen, lower alkyl, or (C₃-C₇)cycloalkyl, where the alkyl orcycloalkyl is optionally substituted with halogen, lower alkoxy, ormono- or di(C₁-C₆)alkylamino; (xi) a group of the formula:

where K, R₁₀, R₁₂, and R₁₇ are as defined above; (xii) a group of theformula:

where each K is as defined as for ii and R₁₀ is defined above; (xii-1) agroup of the formula:

where K, R₁₀, R₁₁, R₁₄, and R₁₅ are as defined above; and (xiii) a groupof the formula:

where K, R₁₀, R₁₂, R₁₄, and R₁₅ are as defined above; (xiv) pyrimidinyl(C₁-C₆alkyl) or pyridyl (C₁-C₅)alkyl; or (xv) a group of the formula:

where R₁₈ is hydrogen, amino, mono-, or di(C₁-C₆)alkylamino, or C₁-C₆alkyl optionally substituted with R₁₉ where R₁₉ represents:

where V and V′ are independently CH or nitrogen; A″ is C₁-C₆ alkylene;and R₂₀ is phenyl, pyridyl, or pyrimidinyl, each of which is optionallymono-, di-, or tri-substituted independently with halogen, hydroxy,C₁-C₆alkoxy, amino, and mono- and di (C₁-C₆) alkylamino.
 7. A compoundof the formula:

or a pharmaceutically acceptable salt thereof, wherein G is loweralkylene having 1-6 carbon atoms; R₅ and R₆ independently representhydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7carbon atoms, or —SO₂R₈, where R₈ is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, oroptionally substituted phenyl; or R₅ and R₆ together with the nitrogenatom to which they are attached form a heterocyclic moiety; Y is (i)lower alkyl having 1-8 carbon atoms or cycloalkyl having 3-7 carbonatoms, any of which may be optionally substituted with one or morehalogen, (C₁-C₆)alkoxy, alkoxyalkoxy where each alkoxy is (C₁-C₆)alkoxy,(C₁-C₆)alkylthio, (C₃-C₇)cycloalkylthio, aryl, heteroaryl, or mono- ordi(C₁-C₆) alkylamino groups; (ii) a group of the formula:

where K is lower alkylene having 1-6 carbon atoms optionally substitutedwith (C₁-C₆)alkyl or alkylene, or a cyclic group of the formula

where K′ independently represents hydrogen or (C₁-C₆)alkyl or alkylene,n is 0, 1, or 2, and m is an integer of from 1 to 5, with the provisothat the sum of n+m is not less than 1 or greater than 5; and R₉ ishydrogen, lower alkyl, or (C₃-C₇)cycloalkyl, where the alkyl orcycloalkyl is optionally substituted with halogen, lower alkoxy, ormono- or dialkylamino; (iii)a group of the formula:

where K is defined as in ii; (iv) a group of the formula:

where K is as defined for ii, and R₁₃ is hydrogen, lower alkyl having1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, where the alkyland cycloalkyl groups are optionally substituted with one or more(C₁-C₆)alkoxy or mono- or di(C₁-C₆) alkylamino groups; and (v) a groupof the formula:

where K is as defined for ii, and R₇ is hydrogen, lower alkyl having 1-6carbon atoms, or cycloalkyl having 3-7 carbon atoms; and (vi) a group ofthe formula:

where K is as defined for ii; and R₁₄ and R₁₅ independently representhydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7carbon atoms, —SO₂R₈ where R₈ carries the definition set forth above, orR₁₄ and R₁₅ together with the nitrogen atom to which they are attachedform a heterocyclic moiety; (vii) a group of the formula:

where K and R₁₅ are as defined above in ii and vi, respectively; (viii)a group of the formula:

where K is as defined for ii; R₁₀ and R₁₀′ are the same or different andare selected from hydrogen, halogen, hydroxy, lower alkoxy having 1-6carbon atoms, or cycloalkoxy having 3-7 carbon atoms; R₁₁, R₁₁′, and R₁₂are the same or different and are selected from hydrogen, halogen,hydroxy, and —OR₄, —CR₇(R₉)NR₅R₆, —CR₇(R₁₆)OR₄,  where R₄ is hydrogen,lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbonatoms, and may be optionally substituted with one or more (C₁-C₆)alkoxyor mono- or di(C₁-C₆)alkylamino groups; R₅ and R₆ carry the definitionsset forth above; and R₉ is hydrogen, lower alkyl, or (C₃-C₇)cycloalkyl,where the alkyl or cycloalkyl is optionally substituted with halogen,lower alkoxy, or mono- or dialkylamino; R₁₆ is hydrogen, lower alkylhaving 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms; or R₁₁and R₁₂ taken together with the atoms to which they are attached form a(hetero)cyclic ring; (ix) a group of the formula:

where K is as defined above for ii; and W is heteroaryl; (x) a group ofthe formula:

where K is as defined for ii; R₁₀ and R₁₁ are as defined for viii, andR₁₇ is hydrogen, lower alkyl, or (C₃-C₇)cycloalkyl, where the alkyl orcycloalkyl is optionally substituted with halogen, lower alkoxy, ormono- or di(C₁-C₆)alkylamino; (xi) a group of the formula:

where K, R₁₀, R₁₂, and R₁₇ are as defined above; (xii) a group of theformula:

where each K is as defined as for ii and R₁₀ is defined above; (xii-1) agroup of the formula:

where K, R₁₀, R₁₁, R₁₄, and R₁₅ are as defined above; and (xiii) a groupof the formula:

where K, R₁₀, R₁₂, R₁₄, and R₁₅ are as defined above; (xiv) pyrimidinyl(C₁-C₆alkyl) or pyridyl (C₁-C₅)alkyl; or (xv) a group of the formula:

where R₁₈ is hydrogen, amino, mono-, or di(C₁-C₆)alkylamino, or C₁-C₆alkyl optionally substituted with R₁₉ where R₁₉ represents:

where V and V′ are independently CH or nitrogen; A″ is C₁-C₆ alkylene;and R₂₀ is phenyl, pyridyl, or pyrimidinyl, each of which is optionallymono-, di-, or tri-substituted independently with halogen, hydroxy,C₁-C₆alkoxy, amino, and mono- and di (C₁-C₆) alkylamino.
 8. A compoundof the formula:

or a pharmaceutically acceptable salt thereof, wherein G is loweralkylene having 1-6 carbon atoms; Y is (i) lower alkyl having 1-8 carbonatoms or cycloalkyl having 3-7 carbon atoms, any of which may beoptionally substituted with one or more halogen, (C₁-C₆)alkoxy,alkoxyalkoxy where each alkoxy is (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,(C₃-C₇)cycloalkylthio, aryl, heteroaryl, or mono- or di(C₁-C₆)alkylamino groups; (ii) a group of the formula:

where K is lower alkylene having 1-6 carbon atoms optionally substitutedwith (C₁-C₆)alkyl or alkylene, or a cyclic group of the formula

where K′ independently represents hydrogen or (C₁-C₆)alkyl or alkylene,n is 0, 1, or 2, and m is an integer of from 1 to 5, with the provisothat the sum of n+m is not less than 1 or greater than 5; and R₉ ishydrogen, lower alkyl, or (C₃-C₇)cycloalkyl, where the alkyl orcycloalkyl is optionally substituted with halogen, lower alkoxy, ormono- or dialkylamino; (iii) a group of the formula:

where K is defined as in ii; (iv) a group of the formula:

where K is as defined for ii, and R₁₃ is hydrogen, lower alkyl having1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, where the alkyland cycloalkyl groups are optionally substituted with one or more(C₁-C₆)alkoxy or mono- or di(C₁-C₆) alkylamino groups; and (v) a groupof the formula:

where K is as defined for ii, and R₇ is hydrogen, lower alkyl having 1-6carbon atoms, or cycloalkyl having 3-7 carbon atoms; and (vi) a group ofthe formula:

where K is as defined for ii; and R₁₄ and R₁₅ independently representhydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7carbon atoms, —SO₂R₈, where R₈ is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, oroptionally substituted phenyl; or R₁₄ and R₁₅ together with the nitrogenatom to which they are attached form a heterocyclic moiety; (vii) agroup of the formula:

where K and R₁₅ are as defined above in ii and vi, respectively; (viii)a group of the formula:

where K is as defined for ii; R₁₀ and R₁₀′ are the same or different andare selected from hydrogen, halogen, hydroxy, lower alkoxy having 1-6carbon atoms, or cycloalkoxy having 3-7 carbon atoms; R₁₁, R₁₁′, and R₁₂are the same or different and are selected from hydrogen, halogen,hydroxy, and —OR₄, —CR₇(R₉)NR₅R₆, —CR₇(R₁₆)OR₄, where R₄ is hydrogen,lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbonatoms, and may be optionally substituted with one or more (C₁-C₆)alkoxyor mono- or di(C₁-C₆)alkylamino groups; R₅ and R₆ independentlyrepresent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkylhaving 3-7 carbon atoms, or —SO₂R₈; or R₅ and R₆ together with thenitrogen atom to which they are attached form a heterocyclic moiety; R₅and R₆ carry the definitions set forth above; and R₉ is hydrogen, loweralkyl, or (C₃-C₇)cycloalkyl, where the alkyl or cycloalkyl is optionallysubstituted with halogen, lower alkoxy, or mono- or dialkylamino; R₁₆ ishydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7carbon atoms; or R₁₁ and R₁₂ taken together with the atoms to which theyare attached form a (hetero)cyclic ring; (ix) a group of the formula:

where K is as defined above for ii; and W is heteroaryl; (x) a group ofthe formula:

where K is as defined for ii; R₁₀ and R₁₁ are as defined for viii, andR₁₇ is hydrogen, lower alkyl, or (C₃-C₇)cycloalkyl, where the alkyl orcycloalkyl is optionally substituted with halogen, lower alkoxy, ormono- or di(C₁-C₆)alkylamino; (xi) a group of the formula:

where K, R₁₀, R₁₂, and R₁₇ are as defined above; (xii) a group of theformula:

where each K is as defined as for ii and R₁₀ is defined above; (xii-1) agroup of the formula:

where K, R₁₀, R₁₁, R₁₄, and R₁₅ are as defined above; and (xiii) a groupof the formula:

where K, R₁₀, R₁₂, R₁₄, and R₁₅ are as defined above; (xiv) pyrimidinyl(C₁-C₆alkyl) or pyridyl (C₁-C₅)alkyl; or (xv) a group of the formula:

where R₁₈ is hydrogen, amino, mono-, or di(C₁-C₆)alkylamino, or C₁-C₆alkyl optionally substituted with R₁₉ where R₁₉ represents:

where V and V′ are independently CH or nitrogen; A″ is C₁-C₆ alkylene;and R₂₀ is phenyl, pyridyl, or pyrimidinyl, each of which is optionallymono-, di-, or tri-substituted independently with halogen, hydroxy,C₁-C₆alkoxy, amino, and mono- and di(C₁-C₆) alkylamino.